As is the case with many Gram-positive pathogens including bacilli and streptococci, staphylococci cause endemic, drug resistant infections over time, for which there are few effective therapeutics. Vancomycin, often considered the last line of defense against methicillin-resistant staphylococcus aureus (MRSA), is now demonstrating an all too familiar path of decreasing effectiveness against rapidly mutating S. aureus. Therefore, there is a critical need for new antibiotics refractory to common resistance mechanisms.
The current arsenal of antibacterial drugs targets only a very narrow spectrum of cellular processes. In particular, a survey recently discovered that antibiotic drug development has produced only one new chemical scaffold in the past 30 years, and that currently prescribed antibiotics collectively disrupt the function of only four bacterial life processes [4]. As a consequence, antibiotic resistance is now emerging at an alarmingly rapid pace, and the most recently approved antibiotics could soon be ineffective [5]. Sustained success in the long-term battle against bacterial pathogens, including MRSA, will require the identification of new chemical scaffolds that target new cellular processes.
Among identified RNA targets, the riboswitch motif has attracted increasing attention. Riboswitches are new, validated targets for novel small molecule intervention against MRSA and other pathogens.75 Riboswitches, functional structures within the 5′-untranslated region (5′UTR) of messenger RNA (mRNA), regulate gene expression in bacteria. Riboswitches are highly selective RNA receptors for the many metabolites that act as cues to control the needs of the organism through termination of transcription or initiation of translation. The conformational change that the riboswitch incurs upon the binding of the metabolite ligand affects the transcription or translation event. Thus, an analog of the natural metabolite could control expression of an essential gene in such a way as to be lethal to the pathogen.75 Other types of riboswitches have a ligand-activated, self-cleavage mechanism that destabilizes the mRNA speeding turn-over.76 Eukaryotic riboswitches activate alternative splicing as a means of controlling gene expression in response to ligand binding. Some bacterial riboswitches are similarly capable.76 Therefore, most riboswitches of bacterial pathogens are unique targets of intervention that do not occur in the host. Rational drug design of small molecule, ligand analogs can be, and have been, pursued against MRSA and other pathogens with the determination of the 3D-structures of the bound and free fragments of mRNA 5′UTR riboswitch.76 
RNA molecules offer significant advantages as drug targets as compared to proteins. As there are far fewer copies of mRNA than protein products, significantly less drug would be required to produce an effect and the mRNA offers a target site relatively more refractory to resistance than that of a traditional protein target. With an insidious pathogen such as MRSA being isolated in war wounds, the importance of identifying new drugs and new drug targets against this multi-drug resistant pathogen cannot be overstated.